P66shc deficient mice develope decreased right heart hypertrophy via a Cyclophilin D dependent mechanism in hypoxia-induced pulmonary hypertension

In acute and chronic hypoxia the response of the pulmonary vasculature is suggested to be regulated via mitochondrial reactive oxygen species (ROS). In response to cellular stress the mitochondrial regulator protein p66shc enhances the ROS-production probably via the pro-apoptotic protein cyclophilin D (CypD). We hypothesized in p66shc-deficient mice lower hypoxic pulmonary vasoconstriction (HPV) and pulmonary hypertension (PH) related to lower hypoxia-induced ROS-production.

HPV was determined in isolated lungs of p66shc and CypD deficient mice, as well as in mice lacking both proteins, and compared to lungs of wild type (WT) mice. The thromboxane mimetic U46619 and potassium chloride (KCl) were used as hypoxia-independent vasoconstrictive stimuli. PH was quantified after exposure of mice to 10% oxygen for 4 weeks by in vivo hemodynamics, and morphometric analysis.

Mice deficient of p66shc, CypD or both proteins exhibited lower responses to acute hypoxia, U46619 and KCl compared to WT mice. In chronic hypoxia-induced pH only p66shc deficient mice exhibited lower right ventricular pressure, right ventricular hypertrophy and hematocrit compared to WT mice. In mice lacking CypD or both proteins, no significant changes of these parameters in chronic hypoxia were detected. There was no change in lung remodeling between all groups.

We conclude that the mitochondrial ROS producing protein p66shc regulates right heart hypertrophy and right ventricular pressure during chronic hypoxia, probably via a CypD dependent mechanism.